Design and Synthesis of 1,4-Amino Alcohol Ligands with a Chiral Cyclopropane Backbone for Asymmetric Diethylzinc Addition to Aromatic Aldehydes

Abstract

A new type of cis-1,4-amino alcohols with a cyclopropane backbone have been developed in three simple steps, from a cheap industrial intermediate for enantioselective asymmetric diethylzinc addition to aromatic aldehydes, under mild conditions to afford corresponding secondary alcohols in high yield with excellent enantioselectivity.

amino alcohols - cyclopropane backbone - organozinc addition - diethylzinc - aromatic aldehydes

References and Notes

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9

cis -Cyclopropane Aminoester 7a-d; Typical Procedure
To a solution of secondary amine (60 mmol) in MeOH (50 mL) was added 5 N HCl-MeOH (4 mL, 20 mmol), followed by 6 (3.12 g, 20 mmol) and NaBH₃CN (1 g, 16 mmol). The resulting solution was stirred at r.t. for 16 h, then concentrated HCl was added until pH <2, and the MeOH was removed in vacuo. The residue was taken up in H₂O (15 mL) and extracted with Et₂O (3 × 20 mL). The aqueous solution was brought to pH >10 with 20% aq NaOH and extracted with Et₂O (5 × 15 mL). The combined extracts were dried over MgSO₄ and concentrated under reduced pressure to give 7a-d in 90-95% yields.
cis -Cyclopropane Aminoalcohol 9a-9d; Typical Procedure
Mg (0.6 g, 25.0 mmol) and a very small amount of I₂ were added to anhyd THF (20 mL). A solution of chlorobenzene (3.14 g, 20 mmol) in THF (10 mL) was added slowly dropwise. Once the reaction began, the rest of the chloro-benzene solution was added at a rate that maintained a gentle reflux. After the addition was complete, the mixture was refluxed for 20 min then cooled to -15 °C. Compound 7
(5 mmol) was dissolved in anhyd THF (5 mL) and added to the prepared Grignard mixture. The resulting solution was stirred at r.t. for 12 h. The reaction was quenched with a sat. solution of NH₄Cl, and the mixture was extracted several times with Et₂O. The combined organic phases was dried over MgSO₄ and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane-EtOAc, 1:2) to afford 9a and 9b as white crystals.
8: Oil; [α]_D ¹⁸ +49.25 (c 0.00201, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.85-0.87 (m, 1 H), 1.06 (s, 3 H), 1.06 (s, 3 H), 2.28 (s, 6 H), 2.33-2.35 (m, 2 H), 3.30-3.34 (m, 1 H), 3.83-3.85 (m, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 15.5, 20.4, 25.5, 29.3, 29.6, 45.0, 55.0, 59.3. HRMS (ESI): m/z calcd for C₉H₂₀NO [M⁺]: 158.1539; found: 158.1543.
9a: Mp 102-103 °C; [α]_D ¹⁸ +63.5 (c 0.01021, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.91 (s, 3 H), 0.93-0.99 (m, 1 H), 1.22 (s, 3 H), 1.75 (d, 1 H, J = 9.5 Hz), 2.14 (s, 6 H), 2.41-2.45 (m, 1 H), 2.62-2.66 (m, 1 H), 7.09-7.11 (m, 2 H), 7.12-7.16 (m, 4 H), 7.22-7.27 (m, 4 H). ¹³C NMR (125 MHz, CDCl₃): δ = 15.6, 20.2, 25.9, 30.2, 38.4, 44.2, 55.0, 125.5, 125.7, 125.9, 126.0, 127.6, 127.7, 149.0, 152.0. HRMS (EI): m/z calcd for C₂₁H₂₈NO [M + H⁺]: 310.2165; found: 310.2164.
9b: Mp 112-113 °C; [α]_D ¹⁸ +14.1 (c 0.01508, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.91 (s, 1 H), 0.92-1.02 (m, 1 H), 1.22 (s, 3 H), 1.61-1.64 (m, 3 H), 1.65-1.74 (m, 3 H), 2.40-2.91 (m, 5 H), 2.93-2.95 (m, 1 H), 7.09-7.16 (m, 2 H), 7.22-7.28 (m, 4 H), 7.50-7.56 (m, 4 H). ¹³C NMR (125 MHz, CDCl₃): δ = 15.5, 20.1, 23.3, 26.5, 30.1, 38.3, 51.3, 52.9, 125.3, 125.7, 125.9, 127.6, 127.7, 149.1, 152.1. HRMS (ESI): m/z calcd for C₂₃H₃₀NO [M + H⁺]: 336.2321; found: 336.2322.
9c: Crystals; mp 162-163 °C; [α]_D ¹⁸ +167.6 (c 0.00816, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.89 (s, 1 H), 1.00-1.05 (m, 1 H), 1.16 (s, 3 H), 1.20-1.37 (m, 4 H), 1.84 (d, 1 H, J = 9.0 Hz), 2.46-2.50 (m, 1 H), 2.56-2.61 (m, 1 H), 7.09-7.14 (m, 2 H), 7.23-7.27 (m, 4 H), 7.52-7.60 (m, 4 H), 7.78 (br, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 15.4, 20.0, 24.1, 25.1, 25.3, 30.3, 37.3, 53.5, 54.7, 125.63, 125.66, 125.74, 125.9, 127.5, 127.7 149.3, 152.0. HRMS (ESI): m/z calcd for C₂₄H₃₂NO [M + H⁺]: 350.2478; found: 350.2479.
9d: Crystals; mp 156-157 °C; [α]_D ¹⁸ +158.5 (c 0.00928, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.94 (s, 1 H), 0.93-1.05 (m, 1 H), 1.17 (s, 3 H), 1.88 (d, 1 H, J = 9.0 Hz), 2.35 (br, 2 H), 2.52 (br, 2 H), 2.56-2.60 (m, 1 H), 2.65-2.69 (m, 2 H), 3.30 (br, 2 H), 3.48-3.52 (m, 2 H), 7.11-7.15 (m, 2 H), 7.24-7.27 (m, 4 H), 7.51-7.61 (m, 4 H). ¹³C NMR (125 MHz, CDCl₃): δ = 15.3, 20.1, 24.5, 30.3, 37.1, 52.64, 54.55, 66.2, 125.5, 125.6, 125.8, 126.2, 127.7, 127.9, 148.9, 151.6. HRMS (ESI): m/z calcd for C₂₃H₃₀NO₂ [M + H⁺]: 352.2271; found: 352.2272.

Diethylzinc Addition to Aldehydes; General Procedure The chiral ligand (0.1 mmol) was dissolved in hexane (3 mL), cooled to -15 °C, and diethylzinc (1.5 M toluene solution; 1.5 mL, 2.2 mmol) was injected. After the mixture was stirred for 20 min, benzaldehyde (0.1 g, 1 mmol) was added dropwise via syringe, and the mixture was stirred for the corresponding reaction time under N₂. The reaction was quenched by the addition of a sat. solution of NH₄Cl (10 mL).The mixture was then extracted with Et₂O (3 × 15 mL), the combined organic extracts were dried, concentrated in vacuo, and the crude products were purified by flash column chromatography (hexane-EtOAc). The ee values of the alcohol products were determined by HPLC on a Chiralcel OD-H column (i-PrOH-hexane) or by GC analysis on a chiral cyclodextrin capillary column. The absolute configuration of the major enantiomer was assigned by comparison of retention time of HPLC or GC with literature data. For literature related to HPLC or GC analysis, please see:

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